Interactions between epigenetics and metabolism in cancers

Abstract

Cancer progression is accompanied by widespread transcriptional changes and metabolic alterations. While it is widely accepted that the origin of cancer can be traced to the mutations that accumulate over time, relatively recent evidence favors a similarly fundamental role for alterations in the epigenome during tumorigenesis. Changes in epigenetics that arise from post-translational modifications of histones and DNA are exploited by cancer cells to upregulate and/or downregulate the expression levels of oncogenes and tumor suppressors, respectively. Although the mechanisms behind these modifications, in particular how they lead to gene silencing and activation, are still being understood, most of the enzymatic machinery of epigenetics require metabolites as substrates or cofactors. As a result, their activities can be influenced by the metabolic state of the cell. The purpose of this review is to give an overview of cancer epigenetics and metabolism and provide examples of where they converge.

Keywords: IDH mutations; NAD metabolism; TCA cycle; Warburg effect; histone modifications; metabolic signaling; α-ketoglutarate and cancer.

Figure 1

Interactions between metabolism and epigenetics. Metabolites that are used as substrates and cofactors for reactions that coordinate epigenetic status (red colors) are centered in this diagram, with the corresponding enzymes that utilize them shown with their chemical reactions. Abbreviation used in this figure: AceCS1, Acetyl-CoA synthetase 1; ACL, ATP-citrate lysase; Ac-CoA, Acetyl-CoA; Acy-protein, Acetylated-protein; Ado, Adenosine; α-KG, α-ketoglutarate; CoA, Co-enzyme; DNMT, DNA methyltransferase; ETC, Electron transport chain; FAD, Flavine adenine dinucleotide; FADH2, Flavin adenine dinucleotide dihydride; GSH, Glutathione; HAT, Histone acetyltransferases; Hcy, Homocystein; HDM, Histone demethylases; 2-HG, 2-hydroxyglutarate; HMT, Histon methyltransferase; IDH1/2, Isocitrate dehydrogenases 1/2; JMDH, JmjC (Jumonji C) domain demethylase; LSD1, Lysine-specific demethylase 1; MAT, Methionine adenosyltransferase; Mut, mutation; NAD⁺, Nicotinamide adenine dinucleotide; NADH, Nicotinamide adenine dinucleotide hydride; SAH, S-adenosylhomocysteine; SAHH, SAH hydrolase; SAM, S-adenosylmethionine; TCA, Tricarboxylic acid; TET2, Ten-eleven translocation 2.